Why do some people fail to respond to exercise?

Regular physical activity is considered key for the prevention of obesity and associated health conditions, but some people reap greater rewards from exercise than others. A new study may have shed light on why this is.

New research suggests that a liver protein may be to blame for exercise resistance.

In a study of both mice and human subjects, researchers found that higher levels of selenoprotein P - a protein secreted by the liver - was associated with reduced exercise capacity and fewer exercise-related benefits.

Study co-author Hirofumi Misu, of the Kanazawa University Graduate School of Medical Sciences in Japan, and colleagues say that their findings indicate that selenoprotein P may be a driver of exercise resistance.

The researchers recently published their findings in the journal Nature Medicine.

According to current guidelines, adults should engage in around 150 minutes of moderate-intensity aerobic activity or 75 minutes of vigorous-intensity aerobic activity each week in order to maintain good health.

However, responsiveness to exercise - in terms of both endurance and metabolic health - can vary widely from person to person.

"In particular, some people show complete non-responsiveness to exercise training in terms of aerobic improvement. Similarly, 15-20 percent of patients with type 2 diabetes show a poor hypoglycemic effect to regular exercise therapy," the authors note.

"These findings indicate that some people suffer from exercise resistance and derive limited benefits from the health-promoting effects of physical exercise."

The precise mechanisms behind exercise resistance, however, have been unclear. Previous research has indicated that selenoprotein P might play a role, so Misu and colleagues set out to investigate this association further.

Selenoprotein P linked to reduced exercise endurance

Firstly, the team assessed the effects of exercise training on two groups of mice: one that was deficient in selenoprotein P, and one group of wild-type mice (the controls).

Both groups ran on a treadmill for 30 minutes per day for 1 month. The researchers found that the selenoprotein P-deficient mice had double the exercise capacity of the wild-type mice.

Furthermore, at the end of the 1-month exercise training, the selenoprotein P-deficient mice demonstrated a larger reduction in blood glucose levels following an injection with the hormone insulin.

The researchers also administered selenoprotein P to wild-type mice prior to 1 month of exercise training.

These mice showed a reduction in phosphorylation of the enzyme AMPK in their muscles. The researchers explain that AMPK phosphorylation is associated with a number of exercise benefits.

Additionally, the researchers found that mice lacking LRP1 - a selenoprotein P receptor in muscles - were unable to absorb selenoprotein P into their muscles. Furthermore, AMPK phosphorylation was not impacted by exercise training.

Findings may lead to exercise-enhancing drugs

Next, Misu and team sought to determine the effects of selenoprotein P on exercise in humans.

The researchers enrolled 31 women who were healthy but who did not engage in regular exercise.

All women took part in 8 weeks of aerobic training, and their maximal oxygen intake was monitored throughout as a measure of exercise endurance.

The team found that women who had high levels of selenoprotein P in their blood prior to the 8-week exercise program demonstrated a lower maximal oxygen intake than those with lower levels of selenoprotein P.

Taken together, the researchers believe that their results indicate that selenoprotein P contributes to exercise resistance by targeting the LRP1 receptor in muscles.

Further research is needed in order to gain a more detailed understating of how selenoprotein P impacts physical activity, but the team believes that this current study may pave the way for drugs that reduce selenoprotein P production to improve exercise endurance.

Misu and colleagues write:

"The current findings suggest that future screening for inhibitors of the [selenoprotein P]-LRP1 axis could identify exercise-enhancing drugs to treat physical-inactivity-associated diseases such as type 2 diabetes."

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